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LL-37-induced host cell cytotoxicity depends on cellular expression of the globular C1q receptor (p33).

Svensson, Daniel LU ; Wilk, Laura LU ; Mörgelin, Matthias LU ; Herwald, Heiko LU and Nilsson, Bengt-Olof LU (2016) In The Biochemical journal 473. p.87-98
Abstract
The human host-defense peptide LL-37 not only displays antimicrobial activity but also immune modulating properties that trigger intracellular signaling events in host cells. Since the cytolytic activity of high LL-37 concentrations affects cell viability, the function of LL-37 requires tight regulation. Eukaryotic cells therefore benefit from protective measures to prevent harmful effects of LL-37. p33, also known as globular C1q receptor, is reported to act as an LL-37 antagonist by binding the peptide thereby reducing its cytotoxic activity. In this report, we show that high levels of endogenous p33 correlate with an increased viability in human cells treated with LL-37. Sub-cellular localization analysis showed p33 distribution at the... (More)
The human host-defense peptide LL-37 not only displays antimicrobial activity but also immune modulating properties that trigger intracellular signaling events in host cells. Since the cytolytic activity of high LL-37 concentrations affects cell viability, the function of LL-37 requires tight regulation. Eukaryotic cells therefore benefit from protective measures to prevent harmful effects of LL-37. p33, also known as globular C1q receptor, is reported to act as an LL-37 antagonist by binding the peptide thereby reducing its cytotoxic activity. In this report, we show that high levels of endogenous p33 correlate with an increased viability in human cells treated with LL-37. Sub-cellular localization analysis showed p33 distribution at the mitochondria, the plasma membrane and in the cytosol. Strikingly, cytosolic over-expression of p33 significantly antagonized detrimental effects of LL-37 on cell fitness, while the reverse effect was observed by siRNA-induced down-regulation of p33. However, modulation of p33 expression had no effect on LL-37-induced plasma membrane pore forming capacity pointing to an intracellular mechanism. A scavenging function of intracellular p33 is further supported by co-immunoprecipitation experiments, showing a direct interaction between intracellular p33 and LL-37. Thus, our findings support an important role of intracellular p33 in maintaining cell viability by counteracting LL-37-induced cytotoxicity. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Biochemical journal
volume
473
pages
87 - 98
publisher
Portland Press Limited
external identifiers
  • pmid:26508735
  • scopus:84955511339
  • wos:000374783900010
ISSN
1470-8728
DOI
10.1042/BJ20150798
language
English
LU publication?
yes
id
69b2160f-eedb-41b5-96ce-18aa5a36218d (old id 8148166)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26508735?dopt=Abstract
date added to LUP
2015-11-04 17:41:26
date last changed
2017-10-22 04:17:36
@article{69b2160f-eedb-41b5-96ce-18aa5a36218d,
  abstract     = {The human host-defense peptide LL-37 not only displays antimicrobial activity but also immune modulating properties that trigger intracellular signaling events in host cells. Since the cytolytic activity of high LL-37 concentrations affects cell viability, the function of LL-37 requires tight regulation. Eukaryotic cells therefore benefit from protective measures to prevent harmful effects of LL-37. p33, also known as globular C1q receptor, is reported to act as an LL-37 antagonist by binding the peptide thereby reducing its cytotoxic activity. In this report, we show that high levels of endogenous p33 correlate with an increased viability in human cells treated with LL-37. Sub-cellular localization analysis showed p33 distribution at the mitochondria, the plasma membrane and in the cytosol. Strikingly, cytosolic over-expression of p33 significantly antagonized detrimental effects of LL-37 on cell fitness, while the reverse effect was observed by siRNA-induced down-regulation of p33. However, modulation of p33 expression had no effect on LL-37-induced plasma membrane pore forming capacity pointing to an intracellular mechanism. A scavenging function of intracellular p33 is further supported by co-immunoprecipitation experiments, showing a direct interaction between intracellular p33 and LL-37. Thus, our findings support an important role of intracellular p33 in maintaining cell viability by counteracting LL-37-induced cytotoxicity.},
  author       = {Svensson, Daniel and Wilk, Laura and Mörgelin, Matthias and Herwald, Heiko and Nilsson, Bengt-Olof},
  issn         = {1470-8728},
  language     = {eng},
  pages        = {87--98},
  publisher    = {Portland Press Limited},
  series       = {The Biochemical journal},
  title        = {LL-37-induced host cell cytotoxicity depends on cellular expression of the globular C1q receptor (p33).},
  url          = {http://dx.doi.org/10.1042/BJ20150798},
  volume       = {473},
  year         = {2016},
}